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Topical estrogen treatment promotes diabetic wound healing. A significant wound healing advantage is observed for estrogen-treated diabetic wounds starting as early as day 6. a, Representative wounds at different days are shown for each group. b, Wound healing rate is expressed as percentage recovery (*; P ¼ .04). N ¼ 6 mice/ group. DAPI, 4 0 ,6-Diamidino-2-phenylindole; EPCs, endothelial progenitor cells; FITC, fluorescein isothiocyanate.
Source publication
Objective:
Endothelial progenitor cells (EPCs) are the key cells of postnatal neovascularization, and mesenchymal stem cells (MSCs) possess pluripotent differentiation capacity and contribute to tissue regeneration and wound healing. Both EPCs and MSCs are critical to the wound repair process, which is hindered in diabetes mellitus. Diabetes has b...
Contexts in source publication
Context 1
... combination of the two colors (red and green converted to yellow) represents recruited BM-derived EPCs. Compared with diabetic wounds treated with placebo cream, wounds treated with estrogen cream had significantly more BM-derived EPCs (Fig 3, a). Five randomly selected high-power fields (magnification Â40) were tallied for each treatment group, and it was found that 75% of newly formed vessels in the estrogen-treated group had incorporated EPCs compared with 27% of those in the placebo-treated group (P ¼ .04; ...
Context 2
... randomly selected high-power fields (magnification Â40) were tallied for each treatment group, and it was found that 75% of newly formed vessels in the estrogen-treated group had incorporated EPCs compared with 27% of those in the placebo-treated group (P ¼ .04; Fig 3, b). This is consistent with less active neovascularization in the placebo-treated mice (Fig 4). ...
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Objective
Although human umbilical cord-derived mesenchymal stem cells (HU-MSCs) have attracted increasing attention because of their pivotal functions in the process of wound healing, the underlying molecular mechanisms have been poorly understood. It has been shown that the TGF-β/Smad signaling pathway plays an important role in the process of sc...
Citations
... "Skin is the first line of defense and barrier against microbial invasion" [1]. "The skin is a host to various transient bacteria contaminants. ...
The risk of wound infection increases with the degree of contamination and it has been estimated that about 50% of wounds contaminated with bacteria become clinically infected. Profile of bacteria isolated from wound infections in patients attending University of Port Harcourt teaching Hospital (UPTH) were investigated. One hundred and eight wound isolates were collected from male and female patients and cultured on nutrient agar, MacConkey and blood agar. Based on morphological and biochemical characteristics of the isolates, Staphylococcus aureus 44(40.75%) was the most prevalent in wound infection in the study area in both male and females followed by Pseudomonas aeruginosa 28(25.9%), Klebsiella spp. 14(13.0%), Proteus spp. 10(9.3%) and Escherichia coli 12(11.1%). The antibiogram showed the presence of multi-drug resistant organisms. The percentage susceptibility of the isolates was: Imipenem (80%), Gentamycin (62%) clindamycin (30%), and levofloxacin (30%). Thus, these antibiotics should be considered as first line drug in the treatment of wound in the area as they were the most effective antibiotics. Prompt and timely treatment is therefore, recommended on the onset of wound infections.
... The delayed wound healing in females is estrogen regulated [17,18] suggesting the role of sex hormones in wound healing. Investigating the role of sex hormones became important with the findings that estrogen significantly enhances wound healing in diabetic mice by increasing the proliferation of endothelial progenitor and mesenchymal stem cells and promoting angiogenesis [19]. Sex hormones can also affect the epidermal permeability barrier which plays a critical role during wound healing [20] and it has been reported that estrogen improves while testosterone declines barrier development during fetal skin development [21]. ...
Treatment of nonhealing diabetic foot ulcers (DFUs) is a major clinical concern and challenge for clinicians. Despite the advancement in treatment strategies, there is no definitive treatment for complicated nonhealing DFUs. Animal models are crucial for understanding pathogenesis and investigating novel therapeutic small molecules and the rodent model is commonly used for research related to cutaneous wound healing. Sexual dimorphism and its effect on the efficacy of sex hormones in enhancing healing in cutaneous wounds using a rodent model have been discussed, however, there is a lack of data related to diabetic foot ulcers. Further, the effects of sexual dimorphism on the issues related to induction of diabetes, differential immune response, type and size of the wound, the effectiveness of topical versus systemic treatment, and molecular mechanisms involved in wound healing like hemostasis, granulation tissue formation, the response of keratinocytes and fibroblasts, inflammation, and skin anatomy are scarcely discussed. Understanding these aspects is of significance and will help in choosing the correct sex, species, and strain of rodents while investigating therapeutic small molecules for DFUs. This review critically summarized these issues and their translational aspects followed by highlighting the effect of sexual dimorphism on these important aspects.
... Male sex was associated with nonhealing of DFU after lower extremity amputation [17]. In animal studies, estrogen treatment was found to promote wound healing in mice with diabetes [18,19]. By contrast, another study reported that only estrogen treatment did not promote wound healing in mice with diabetes [20]. ...
... Estrogen promotes cutaneous wound healing in db/db mice The levels of ovarian steroid hormones, which include serum estradiol and progesterone, were consistently lower in db/db mice than in their littermate controls [28]. Zhuge et al. showed that the uterine weight of estrogen-treated db/db mice was significantly higher than that of placebo-treated db/db mice [18]. In the current study, the uterine weight in the db/db + estrogen group was significantly higher than those in the db/db, db/db + vehicle, and WT groups. ...
... Estrogen promotes cutaneous wound healing in db/db mice neovascularization in db/db mice with type 2 diabetes [18], and the administration of estrogen improved vascular outcomes in rats with STZ-induced type 1 diabetes [43]. Therefore, the present study showed that delayed cutaneous wound healing improved after estrogen treatment in mice with type 2 diabetes. ...
Female sex hormones are beneficial effects for wound healing. However, till date, whether topical estrogen application can promote cutaneous wound healing in diabetes remains unclear. Therefore, the present study aimed to validate the effect of topical estrogen application on cutaneous wound healing in a type 2 diabetes db/db mice model. In total, 22 db/db female mice with type 2 diabetes and eight C57BL/6J female mice were subjected to two full-thickness wound injuries. The mice were divided into the db/db, db/db + estrogen, db/db + vehicle, and wild type (WT) groups. Wound healing was assessed until day 14. The db/db group had a significantly high wound area ratio (wound area/initial wound area) on days 3–14 and a significantly low re-epithelialization ratio on days 7 and 14. Moreover, their angiogenesis ratio was significantly low on day 7 and high on day 14. In contrast, compared with the db/db group, the db/db + estrogen group had a significantly lower wound area ratio on days 1–14 and angiogenesis ratio on day 14, thereby indicating early withdrawal of new blood vessels, as well as a significantly higher re-epithelialization ratio on days 7 and 14 and Ym1 ⁺ M2 macrophage/macrophage ratio on day 7. Moreover, microarray analysis showed that the top 10 upregulated or downregulated genes in the db/db group were reversed by estrogen treatment, particularly on day 14, in comparison with the WT group. Thus, topical estrogen application reduced the wound area, promoted re-epithelialization and angiogenesis, and increased the number of M2 macrophages in mice with type 2 diabetes. Furthermore, it improved the differential regulation of genes in db/db mice. Therefore, such treatment can enhance cutaneous wound healing in female mice with type 2 diabetes.
... Estrogen has anti-inflammatory activity and can antagonize the stimulation of the lipopolysaccharide component (LPS) of the cell wall of Gram-negative bacteria. Studies have confirmed that estrogen can accelerate wound healing, by reducing wound macrophage infiltration, inhibiting LPS-induced inflammatory signals, promoting the migration of mouse keratinocytes in vitro, promoting wound formation in diabetic mice, improving insulin sensitivity, and stimulating glucose to ingest [30][31][32][33]. Estrogen may become a new therapeutic target for diabetic anal fistula wounds. ...
Objective. Using network pharmacology research methods to explore the healing mechanism of American cockroach extract to accelerate wound healing after diabetic anal fistula surgery. Method. The main chemical constituents of extracts from Periplaneta americana were collected by literature retrieval. Chemical composition and targets related to diabetic anal fistula wound could be predicted based on PubChem, Swiss Target Prediction, OMIM, and GeneCards databases, and the putative targets of Periplaneta americana extraction (PAE) for diabetic anal fistula wound were obtained by Venn diagram. These common targets were predicted using the String database for protein-protein interaction (PPI) network and then screening key genes through Cytohubba. Meanwhile, the above targets were analyzed using the DAVID database for gene ontology (GO) enrichment analyses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) path enrichment analyses. Results. A total of 12 chemical components of PAE were obtained by literature retrieval, and 61 therapeutic targets that may accelerate the healing of diabetic anal fistula wounds were predicted by the database. According to PPI network analysis, PAE accelerates wound healing after diabetic anal fistula surgery which may be related to proteins such as AKT1, VEGFA, EGFR, CASP3, STAT3, MAPK1, TNF, JUN, ESR1, and MMP9. GO analysis results show that targets of PAE to promote wound healing were mainly involved in biological processes such as cell proliferation, macrophage differentiation, angiogenesis, and response to hypoxia. KEGG analysis showed that the target genes were mainly concentrated in the PI3K-Akt signaling pathway, HIF-1 signaling pathway, and estrogen signaling pathway. Conclusion. Periplaneta americana extract regulates multiple targets and multiple pathways to promote wound healing after diabetic anal fistula surgery. PI3K-Akt signaling pathway, HIF-1 signaling pathway, and sex hormone signaling pathway may be key pathways in the process of Periplaneta americana extract promoting wound healing.
1. Introduction
Anal fistula is a tube located between the perianal skin and the rectum. It is caused by chronic infection and epithelialization of the drainage tube [1]. It is one of the common diseases in the anorectal department, and surgery is the first choice. Epidemiological data show that the total number of diabetes patients in the world was 463 million in 2019, and it is estimated that it will rise to 578 million in 2030 and 700 million in 2045 [2]. Prolonged generation of pathological blood sugar elevation in the body can lead to the sequel of advanced glycation end products in the body, which provide a good nutritional environment for the growth of bacteria, and easily cause wound tissue infection and necrosis, and hinder wound healing. Diabetes is a risk factor leading to slow wound healing after anal fistula surgery [3–5].
In wound healing, some herbal and animal Chinese medicines have very good clinical effects [6–8], and Quyushengxin formula can promote mucosal healing in UC patients [9]. In traditional Persian medicine [10], the plants’ hard tissues such as roots or barks were boiled in water. Subsequently, the resulting extract was boiled in combination with sesame or olive oil until its water part was lost to exert its efficacy. Periplaneta americana (PA), the American cockroach, has the largest body size in the family Blattidae. It is an animal traditional Chinese medicine. Physiological and pharmacological studies have demonstrated that PA constituents have favorable tissue-repairing, antibacterial, antitumor, and immunity-enhancing activities [11]. Additionally, this insect has been widely used for the treatment of various wounds, ulcers, fistulas, bedsores, and burns [12]. Consequently, the formulation of many TCM preparations, among them, Kangfuxin (Periplaneta americana extract, PAE), is a liquid preparation that includes ingredients from PA that has been used to treat different skin or mucosa injuries in China for more than 40 years. Our team applied PAE to wounds after anorectal diseases in the early years and found that the effect of promoting wound healing was very good [13]. Besides, it has been reported that PAE can promote postoperative wound healing in diabetic patients [14], but there are few studies on postoperative wounds in diabetes patients with anal fistula. We hypothesize that PAE can promote postoperative wound healing in diabetes patients with anal fistula, and its mechanism for promoting healing remains to be further studied.
Network pharmacology is an emerging research method first proposed by Andrew L Hopkins in Nature Biotechnology in 2007 [15]. It is based on drug databases, disease databases, gene pleiotropy, computational biology, and network biology analysis, etc., to construct a “drug-target-disease‐pathway” interaction network and to comprehensively analyze the relationship of drug components, genes, and diseases, thereby revealing the intervention mechanism of drugs on the disease. Its holistic and dynamic characteristics, the principle of multitarget, and multichannel administration are highly consistent with the holistic view of traditional Chinese medicine and the treatment principle of syndrome differentiation. The purpose of this study is to use the research methods of network pharmacology to initially find the target of PAE in repairing postoperative wounds of diabetes patients with anal fistula and to provide a theoretical basis for further application.
2. Materials and Methods
2.1. Effective Chemical Ingredient Screening
There are rarely studies on the chemical components of Periplaneta americana, and no relevant chemical ingredients are included in the TCMSP database (http://ibts.hkbu.edu.hk/LSP/Tcmsp.php). We use “American Cockroach (Periplaneta americana),” “KANG FU XIN YE,” as the keyword to retrieve in the PubMed and CNKI databases. 12 compounds related to wound healing were screened out through literature research [11, 12, 16]: cytosine, cytidine, thymine, uracil, guanosine, adenine, hypoxanthine, inosine, uridine, cyclo-(L-Val-L-Pro), arbutin, and (E)-3-hexenyl-β-D-glucopyranoside.
2.2. Target Prediction of Drug
The compound was imported into PubChem (https://pubchem.ncbi.nlm.nih.gov/) to obtain SMILES, and the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) was used to predict potential targets and limit the species: Homo sapiens. The target point of the drug component was obtained.
2.3. Drug-Disease-Related Target Screening
Disease targets are derived from the Human Mendelian Genetic Database (OMIM) (http://www.omim.org/) and the human genome annotation database (GeneCards) (https://www.genecards.org/) with the keywords “diabetic anal fistula wound.” Then, the genes of the two databases were integrated to remove the duplicates to obtain the relevant targets of diabetic anal fistula wounds. Finally, the Venn diagram was used to find out the intersection genes of disease target genes and drug target genes, that is, the potential target of American cockroach extract in treating diabetic anal fistula wounds.
2.4. Network Construction and Analyses
2.4.1. Construction of the Compound-Target Network
The drug components of PAE and their potential targets for promoting wound healing after diabetic anal fistula surgery were introduced into Cytoscape 3.1.1 to construct a network diagram of active ingredients and disease targets. The network was analyzed through the network analysis function. The degree, closeness, and betweenness are important parameters for evaluating active ingredients and targets.
2.4.2. Construction of Protein-Protein Interaction Network
The intersection gene was uploaded to the String database (https://string-db.org/), the species were limited to “Homo sapiens,” the minimum interaction threshold was set to “medium confidence” 0.4, and nodes without network connections were hidden. The protein-protein interaction (PPI) network diagram was obtained. The Cytoscape 3.1.1 software was used to realize the visualization of the network, and then, the Cytohubba plug-in was used to screen the top 10 key genes according to degree.
2.4.3. GO and KEGG Analyses
The potential targets of PAE in promoting wound healing after diabetic anal fistula surgery were analyzed by Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment in the Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8, value <0.05, and the species selected were “Homo sapiens,” elucidating the potential healing mechanism of American cockroach extract in the treatment of diabetic anal fistula wounds.
3. Results
3.1. Targets of Active Ingredients in Periplaneta americana
There are a total of 797 predicted targets for 12 compounds, including 6 targets in cytosine, 100 in cytidine, 19 in thymine, 25 in uracil, 100 in guanosine, 32 in adenine, 32 targets in hypoxanthine, 100 in inosine, 100 in uridine, 100 in cyclo-(L-Val-L-Pro), 86 in arbutin targets, and 97 targets in (E)-3-hexenyl-β-D-glucopyranoside. The 12 compound target genes were merged, and then the duplicate genes were deleted to obtain 370 drug targets.
3.2. Periplaneta americana Treatment Targets for Diabetic Anal Fistula Wounds
693 targets related to diabetic anal fistula wounds were retrieved through OMIM and GeneCards disease databases. 61 targets for the treatment of diabetic anal fistula wounds in Periplaneta americana were obtained by the Venn diagram online tool (Figure 1).
... Littermate wild-type mice (C57BL/6J background, 6-8 weeks old) were used as controls. We only used male mice in the study considering that estrogen in females may influence the effect of the bone marrow-derived progenitor cells [34]. The mice were housed with free access to food and water in 12-h dark/light cycle. ...
Background:
The distal airways of the lung and bone marrow are innervated by the vagus nerve. Vagal α7nAChR signaling plays a key role in regulating lung infection and inflammation; however, whether this pathway regulates α7nAChR+Sca1+ cells during lung injury repair remains unknown. We hypothesized that vagal α7nAChR signaling controls α7nAChR+Sca1+ cells, which contribute to the resolution of lung injury.
Methods:
Pneumonia was induced by intratracheal challenge with E. coli. The bone marrow mononuclear cells (BM-MNCs) were isolated from the bone marrow of pneumonia mice for immunofluorescence. The bone marrow, blood, BAL, and lung cells were isolated for flow cytometric analysis by labeling with anti-Sca1, VE-cadherin, p-Akt1, or Flk1 antibodies. Immunofluorescence was also used to examine the coexpression of α7nAChR, VE-cadherin, and p-Akt1. Sham, vagotomized, α7nAChR knockout, and Akt1 knockout mice were infected with E. coli to study the regulatory role of vagal α7nAChR signaling and Akt1 in Sca1+ cells.
Results:
During pneumonia, BM-MNCs were enriched with α7nAChR+Sca1+ cells, and this cell population proliferated. Transplantation of pneumonia BM-MNCs could mitigate lung injury and increase engraftment in recipient pneumonia lungs. Activation of α7nAChR by its agonist could boost α7nAChR+Sca1+ cells in the bone marrow, peripheral blood, and bronchoalveolar lavage (BAL) in pneumonia. Immunofluorescence revealed that α7nAChR, VE-cadherin, and p-Akt1 were coexpressed in the bone marrow cells. Vagotomy could reduce α7nAChR+VE-cadherin+ and VE-cadherin+p-Akt1+ cells in the bone marrow in pneumonia. Knockout of α7nAChR reduced VE-cadherin+ cells and p-Akt1+ cells in the bone marrow. Deletion of Akt1 reduced Sca1+ cells in the bone marrow and BAL. More importantly, 91.3 ± 4.9% bone marrow and 77.8 ± 4.9% lung α7nAChR+Sca1+VE-cadherin+ cells expressed Flk1, which is a key marker of endothelial progenitor cells (EPCs). Vagotomy reduced α7nAChR+Sca1+VE-cadherin+p-Akt1+ cells in the bone marrow and lung from pneumonia mice. Treatment with cultured EPCs reduced ELW compared to PBS treatment in E. coli pneumonia mice at 48 h. The ELW was further reduced by treatment with EPCs combining with α7nAChR agonist-PHA568487 compared to EPC treatments only.
Conclusions:
Vagal α7nAChR signaling regulates α7nAChR+Sca1+VE-cadherin+ EPCs via phosphorylation of Akt1 during lung injury repair in pneumonia.
... Then, sterile silicone rings were placed on the vascular-rich site, and the varying liposomal formulations were added to the silicone ring at a final concentration of 0.2 μM vinorelbine and 10μM dioscin, and the windows were then closed. 27 After 48 h of incubation, the CAM was captured with a digital camera and the blood vessel area was analyzed using image pro plus 5.0 software. ...
Background:
Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM) and angiogenesis results in invasion, migration and relapse.
Purpose:
The objective of this study was to construct a novel CPP (mmp) modified vinorelbine and dioscin liposomes by two new functional materials, DSPE-PEG2000-MAL and CPP-PVGLIG-PEG5000, to destroy VM channels, angiogenesis, EMT and inhibit invasion and migration.
Methods and results:
The targeting liposomes could be enriched in tumor sites through passive targeting, and the positively charged CPP was exposed and enhanced active targeting via electrostatic adsorption after being hydrolyzed by MMP2 enzymes overexpressed in the tumor microenvironment. We found that CPP (mmp) modified vinorelbine and dioscin liposomes with the ideal physicochemical properties and exhibited enhanced cellular uptake. In vitro and in vivo results showed that CPP (mmp) modified vinorelbine and dioscin liposomes could inhibit migration and invasion of A549 cells, destroy VM channels formation and angiogenesis, and block the EMT process. Pharmacodynamic studies showed that the targeting liposomes had obvious accumulations in tumor sites and magnificent antitumor efficiency.
Conclusion:
CPP (mmp) modified vinorelbine plus dioscin liposomes could provide a new strategy for NSCLC.
... Topical application in diabetic mice [46] -Peripheral blood mononuclear cells Direct application Application of cell sheets composed of fibroblasts and PBMCs in diabetic mice [47,48] Topical application of APOSEC in healthy volunteers [49] Endothelial progenitors Recruitment Local administration of recombinant SDF1 in diabetic mice [50] Pharmacological inhibition of DPP4 in diabetic wounds [51] Modulation Topical administration of estrogens in diabetic mice [52] -Direct application Local transplantation of human EPCs in immunocompromised mice [53] or model of burn wound in pigs [54] Intra-arterial delivery of CD133 + EPCs in diabetic foot patients [55] Mobilization and Direct application -Systemic administration of GM-CSF followed by isolation of CD34 + /VEGFR2 + cells and intramuscular injection in non-healing foot in diabetic patients [56] Stromal vascular fraction Direct application SVF seeding on human epidermal skin substitutes applied in nude rats [57] Direct application of autologous SVF on diabetic ulcers [58,59] or post-traumatic lower extremity ulcers [60] Figure 1. The figure shows examples of cellular therapies proposed and exploited for the treatment of non-healing wounds, grouped according to four main approaches: cell mobilization into the circulation, cell recruitment to the wound site, modulation of cell function/activity, and direct application of cells to the wound site. ...
... Other studies have tried to enhance the EPC viability and proliferation at the site of the wound. Starting from the evidence that angiogenesis during the menstrual cycle largely depends on estrogen and that the latter increases the colony-forming capacity of EPCs in culture [160,161], the topical administration of estrogen has been successfully validated as a treatment to accelerate wound healing in diabetic mice [52]. However, to what extent this therapeutic effect can be ascribed to EPCs or other estrogen-responsive cells participating in the healing process (i.e., keratinocytes and fibroblasts) remains an open question [162][163][164]. ...
With the increased prevalence of chronic diseases, non-healing wounds place a significant burden on the health system and the quality of life of affected patients. Non-healing wounds are full-thickness skin lesions that persist for months or years. While several factors contribute to their pathogenesis, all non-healing wounds consistently demonstrate inadequate vascularization, resulting in the poor supply of oxygen, nutrients, and growth factors at the level of the lesion. Most existing therapies rely on the use of dermal substitutes, which help the re-epithelialization of the lesion by mimicking a pro-regenerative extracellular matrix. However, in most patients, this approach is not efficient, as non-healing wounds principally affect individuals afflicted with vascular disorders, such as peripheral artery disease and/or diabetes. Over the last 25 years, innovative therapies have been proposed with the aim of fostering the regenerative potential of multiple immune cell types. This can be achieved by promoting cell mobilization into the circulation, their recruitment to the wound site, modulation of their local activity, or their direct injection into the wound. In this review, we summarize preclinical and clinical studies that have explored the potential of various populations of immune cells to promote skin regeneration in non-healing wounds and critically discuss the current limitations that prevent the adoption of these therapies in the clinics.
... Accordingly, topical estrogens accelerate wound healing, favor the formation of capillary-like structures in endothelial cells, stimulate the release of PDGF by macrophages and TGFβ1 by fibroblasts and promote wound contraction, formation of granulation tissue and collagen deposition [48]. More recent data indicate that estrogens enhance wound closure and reepithelization also in diabetic mice and this effect is mediated by increased epithelial precursor cells and mesenchymal stem cells which contribute to neo-angiogenesis and tissue regeneration, respectively [49]. Interestingly, the migratory promoting effect of keratinocytes that can produce re-epithelization seems to involve mainly estrogen receptor β (ERβ) [50] and accordingly genistein, an isoflavone acting selectively on ERβ, displays anti-inflammatory and antioxidant activity while improving wound healing in diabetic mice [51]. ...
Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing.
... A large amount of inflammatory mediators, such as tumor necrosis factor (TNF)-a and interleukin (IL)-6, secreted by cells were released into the wound site and subsequently prevented the cell proliferation and migration required for diabetic wound healing [5]. Furthermore, over-activation of inflammation increased matrix metalloproteinase (MMP)-9 expression [6,7], which resulted in rapid degradation of native collagen, fibronectin, and elastin, thus delaying the diabetic wound-healing process [8]. ...
Chronic, subclinical inflammation was often observed in the diabetic wound area, causing inadequate and delayed wound-healing effects by failing to initiate cell migration, proliferation, and extracellular matrix deposition. Therefore, we presented macrophage-derived exosomes (Exos) and explored their potential for inhibiting inflammation and accelerating diabetic wound healing in a skin defect, diabetic rat model. A thorough investigation demonstrated that Exos exerted anti-inflammatory effects by inhibiting the secretion of pro-inflammatory enzymes and cytokines. Furthermore, they accelerated the wound-healing process by inducing endothelial cell proliferation and migration to improve angiogenesis and re-epithelialization in diabetic wounds.
... Recently autologous and allogeneic MSCs were both transplanted into humans to promote the regeneration of skin defects, and several clinical trials have been conducted involving the efficacy of MSC transplantation alone or combined with grafts for treating severe skin burns [215], perianal fistula [216], non-healing ulcers due to diabetes [217], dystrophic epidermolysis bullosa [218], and radiation-related skin lesions [219]. Estrogen treatment repairs diabetic wounds by significantly increasing MSC viability and proliferation and promoting neovascularization [220]. For appendage regeneration, Sheng et al. [221] reported the successful transplantation of MSCs to regenerate functional sweat glands in five patients in 2009, followed by subsequent reports of this procedure was successfully performed, with ectodysplasin-modified MSCs [207] and BMSCs on EGF-loaded scaffolds [222] demonstrated to differentiate into the functional sweat-gland cells. ...
In recent decades, the biomedical applications of mesenchymal stem cells (MSCs) have attracted increasing attention. MSCs are easily extracted from the bone marrow, fat, and synovium, and differentiate into various cell lineages according to the requirements of specific biomedical applications. As MSCs do not express significant histocompatibility complexes and immune stimulating molecules, they are not detected by immune surveillance and do not lead to graft rejection after transplantation. These properties make them competent biomedical candidates, especially in tissue engineering. We present a brief overview of MSC extraction methods and subsequent potential for differentiation, and a comprehensive overview of their preclinical and clinical applications in regenerative medicine, and discuss future challenges.
